The Brain Circuitry of Bipolar Disorder: A View from Brain Scanning Research

thank you so much for that very kind introduction thank you so much to be BRF for this wonderful and humbling honor of the Colvin award and thank you to all who are attending here with the interest in the research I'll be telling you about a program of research that we're doing on the brain and bipolar disorder and it's especially meaningful for me to be giving this talk at this be BRF symposium as most of this work would not be possible if it weren't for be PRF much of the work that I'll tell you about I was able to initiate because I had an RCD BRF Young Investigator award and then I was able to grow the research and continue and then to grow and expand the research having received a B BRF independent investigator award and then as the program continued to grow there were young investigators who join the group and their work thrived because they then received Young Investigator awards and now they're expanding their own programs so I'm really particularly delighted to give this talk here today so this talk will have three different parts to it in the first part I'll be talking a little bit about bipolar disorder and in particular kind of talking about it from the perspective of giving you the ingredients to see kind of where what we were thinking about and bipolar disorder to develop a brain model for the disorder in the second part of the talk I'll be presenting that brain model the neurodevelopmental model as dr. Hirsch felt was alluding to and I'll be showing you then images from our brain scanning research so I'll be providing the evidence for that model and then third in the last part of the talk I'll be talking about some of the new work in which we are the work to try to see what there could be in terms of new clues for new directions for treatment and also for the prevention of difficult symptoms and the suffering of mood disorders okay so first to tell you a little bit about some of the symptoms of bipolar disorder but particularly to be thinking about what symptoms we were thinking about as we try to build a brain model for bipolar disorder so as I have kind of boxed in in green as you know in the mood disorders what is central to the mood disorders are more extreme and sustained changes in emotions so in depression there's the sadness the lows of depression in mania which is the hallmark for a bipolar disorder diagnosis there is the elevated mood and that can be you forea or it can be an uncharacteristic irritability and so these changes and emotions are central to bipolar disorder so when we're trying to think about a brain model we think about central to that brain model the brain circuitry that is involved in regulating emotions however and as I've shown on the slide here also very important to the mood disorders are this other broad range of symptoms and they span from symptoms that relate to some of the most primitive parts of the brain key parts of the brain so one's involved for example in sleep and appetite the hypothalamus I'll tell you about briefly and you can almost kind of March up the nervous system from these inner deep were kind of primitive essential brain structures all the way through to the outside of the brain the prefrontal cortex is involved in some of the most high order or executive functions of the brain which could also be affected in bipolar disorder and so if we're going to build a brain model for bipolar disorder we need one that can account for this kind of centrality of emotional dysregulation but then also for this broad range of symptoms here I have kind of an illustration of a squish I'm a life course of bipolar disorder untreated there's just one type of example and what I have going along horizontally is age going up is higher manic symptoms going down more depressed symptoms and what you can see in this potential example is that before puberty maybe there were already some symptoms maybe there were lower symptoms or not recognized to be symptoms of a mood disorder but then around puberty or after which is often the case now a mood disorder starting to declare itself and that is often with depressive symptoms untreated there can be an increase in the severity and the frequency of the episodes so well goal for us with treatment is to try to decrease that the severity of the episodes and their frequency so that someone can go on to do everything that they wish to do in life and what I'll allude to as well and come back to themes about is that bipolar disorder can have this progressive aspect and so one of the focus of our program is to try to figure out ways to intervene to prevent this progression and to improve prognosis bipolar disorder is also associated with a high risk of suicide as many as 50% of individuals with bipolar disorder may attempt suicide and it's been estimated that as high as 10 or 15 to 20 percent will lose their lives to suicide suicidal thoughts and behaviors often develop at similar times that we start to see bipolar disorder express itself in the teenage and adolescent years and so kind of ghosts are studying the changes in the adolescent brain in bipolar disorder kind of go hand in hand with our studying how suicide thoughts and behaviors development but I think in some ways the most important part of this slide is that we already have evidence particularly in adults that treatments can help to lower the risk for suicide that's that most of the studies have been primarily with lithium and in adults but I think taken together with the idea that if we can prevent the episodes and the progression we can really improve prognosis and so on and go on to live the life that they like to live in whatever way they would like and that we could also decrease not just the suffering but also this risk of suicide really drives us in our work to try to go as fast as we can to find some answers okay so towards that I'll tell you some about the brain model that we have for bipolar disorder and so when we first started out and dr. Hirschfeld mentioned that initially I was in New York not too far from here at Cornell than just Cornell now Weill Cornell and in trying to think about this when there weren't quite yet or they were just emerging the tools to be able to look inside the brain of someone actually experiencing symptoms we turned then we turn to neurology or behavioral neurology to see for example if someone had a lesion in the brain had had a stroke or brain trauma where that lesion was that might lead to symptoms of bipolar disorder and in fact there had been descriptions since at least the 1800s of individuals who had had lesions in their brain particularly in the frontal part of their brain and particularly in this lower part I'll be referring to the ventral pre frontal part of the brain and interestingly there was also a laterality to it and so individuals who had lesions on the left in the left hemisphere tended to get depressed whereas if they were going to get manic after an injury often the lesion was on the right and there's an idea that in the brain and evidence for this that there's some difference in which side of the brain which hemisphere more processes negative or positive emotions so the idea for example is that in the right hemisphere negative emotions are processed more so if you have a lesion a problem or lower activity in the right side you kind of have a release or an exaggeration of the emotions of the other side and I'll go back to that but for now potentially remember that would predict that in mania in bipolar disorder we would see decreases in right and particularly ventral prefrontal cortex so here is an illustration of the brain I'll keep going back to the brain is a line the same way that I'm standing and it's cut then right down down the middle and here in the front is the frontal cortex and again this lower part we call the ventral prefrontal cortex I have it colored here in a cool blue color with the reminder that often what we saw early on were particularly related to mania were decreases in activity that's what we were predicting also very important these structures work within circuits it's also very important in this circuit key in the circuit is a structure called the amygdala and that's a structure this is the temporal lobe of the brain it's a structure deep in the temporal lobe it's named after the Greek word for almond that's amygdala and as I alluded to structures that are deeper in the brain tend to be more processed more basic or primitive functions so the amygdala has a more kind of basic role in emotional reactions to different kinds of stimuli in contrast now the folded executive prefrontal cortex helps to take in all sorts of information and then feed back to the amygdala to allow for the most adaptive responses and so I've got them now colored here the amygdala in red because they think it's a hot area and bipolar disorder with elevated activity and then the cool blue frontal cortex and then importantly we're thinking more and more about the connections between the two and so there are major connections between ventral prefrontal cortex and amygdala and those are inhibitory and that's often how the brain works is that high destructors like the frontal cortex we'll think about things and then try to put the brakes on other areas reactive areas of the brain to help for behavior to be more adaptive and so knowing that you can kind of imagine that you could wind up with this pattern of higher amygdala lower prefrontal cortex either through a problem in the amygdala a problem in the Metro prefrontal cortex or a problem in the connection and I'll be showing you examples of all three of those in the talk I just want to also say I'm going to be very focused on those areas but there are many more widespread connections that are very important to distributed in the brain so for example I mentioned the hypothalamus amygdala and ventral prefrontal cortex highly connected to the hypothalamus and that's important because the hypothalamus is important in sleep appetite sex drives all effected and mood disorders and perhaps you can kind of imagine if you have problems in that core emotional circuitry amygdala prefrontal and it's connections that you could also have consequences in also in hypothalamus and the regulation of those other kind of functions other parts of the brain are involved and doctor Phillips in particular we'll be talking about ventral striatum and it's connections and motivated behavior in the talk that follows mine so I'll be showing you for the most part data from MRI scanning that's a picture of our MRI scanner it's pretty similar to an MRI scanner if you went for clinical reasons to get an MRI scanner to scan it's a little bit stronger and we use very particular kinds of computer algorithms to obtain and to analyze the data and I'll be showing you three different types of data that we get in one scanning session so first we get high-resolution structural scans so we can see the size and the shape of brain structures in their volume second we get functional scans so we can look at brain activity we can see what brain activity is in a particular region and also how brain regions work together in a brain circuit and then finally we can get something called diffusion tensor imaging where we can actually look at the structural integrity of those connections those white matter coated connections so we began this work this is the only slide that I will show you that's not fMRI this is positron emission tomography and back from the New York days but this was particularly exciting to us as this was one of the first times there was a look inside the brain of someone with bipolar disorder while they were experiencing manic symptoms and indeed what we saw was that there was decreased activity in the frontal lobe and it was also on the right keep flipping brains around and I know that looks like it's on the left but that's actually on the right side of the brain so consistent with our hypotheses I then went to Yale it's been almost 20 years now and began the work with MRI and we saw some of the same findings new subjects new techniques so what I'm going to be doing is I'm going to be flipping around in the brain a little bit but it here's what's excuse me here's that the brain the way we had before if you can kind of imagine a slice or the brain this way then on these pictures this part of this is the front the frontal part of the brain and so what we saw again in mania where decreases in the right we then saw differences and depression on the left and then again all this workers and adults now we also saw some decreases in this part of the brain and adults with bipolar disorder when they weren't experiencing mood acute mood symptoms of the disorder suggesting maybe there's something about some difficulties in ventral prefrontal cortex that makes them vulnerable to having the mood states so how how could we get there from from a neurodevelopmental point of view and so when we started out with our hypotheses one of the things that I was very interested in is that the brain doesn't all devel all parts of the brain don't develop at the same time don't fully mature at the same time right those the the structures in the brain that are deep that are important in very basic functions it's very important for them to develop and mature early because those functions are very essential to life but then those later to evolve parts of the brain that have those more executive roles that taken much more complex information those are later to mature and continue to mature in adolescence and adulthood so the thought that we had so here first four so for example in amygdala in this deep region of the brain this is sort of cartooning it but compared to prefrontal cortex there's relative stability in the amygdala in terms of its volume by after puberty in contrast to prefrontal cortex where for puberty there's the sprouting and the growing of neuronal connections and then after puberty the pruning back or the decreasing of those connections in the service of more adaptive and refined behavioral responses and so what we wondered then is would we see this kind of sequence of emergence of the brain differences in bipolar disorder that parallel the sequence of development and so we hypothesized then that in amygdala we might already be able to detect differences in the amygdala by adolescence whereas in the frontal cortex there might be a progressive divergence in the structure and function of the frontal cortex over adolescence and young adulthood so that we'd really see the most the most exaggerated differences and ones that are typical of adults not fully emerge not fully manifest until young adulthood and this idea is important in the sense that if there are there's this progression of differences and this is a adolescence for example is one critical period and you'll be hearing a lot about critical periods in the talks today then it's very important for us to be able to identify the risk things that could steer this development well of course these trajectories off course early life stress substance abuse and other potential things that steer it further off course that we need to prevent but also we're learning more and more about how plastic the brain is and how to help enhance brain plasticity and that brings tremendous hope that we're gonna be able to find ways to help to steer the trajectory back on track to improve prognosis ok so to show you some of the data again the amygdala where we're hypothesizing early abnormalities and so we saw an amygdala our decreases in the volume and bipolar disorder and indeed we saw it adolescents as well as an adult's we also saw that red hot an amygdala the increases in the responses of the amygdala to emotional stimuli and those were correlated such that those are the smallest amygdala had the most excessive responses and that gives us some clues about what might be happening in the amygdala and we're now following that up at ultra high magnetic field research that we've started to do at Yale frontal cortex in terms of development what we thought we might see progression that's indeed what we saw so what you can see here in ventral prefrontal volume some decreases in adolescence but larger decreases by young adulthood and then these images and two different samples of adolescents and young adults who are studied over time with repeated scans we saw a greater decreases over time in those areas of frontal cortex and the adolescents with bipolar disorder than the adolescents without so what about the connections that some of the newer work that we're doing and there there are some implications that those connections that grow from and make to look to prefrontal cortex that some of the differences in those connections may be present but may also be progressing and just a note about changes with development in the white matter so again whoops again the reminder about the gray matter changes the white matter changes seem to occur for a longer period of time so seem to continue to be increasing into the 40s for example and so there may even be longer periods of opportunity to make a change in that development of the connections and we're interested both in that those developmental changes and that I won't be talking so much about today but we're also interested in thinking about the aging processes that occur after that peak so we use diffusion tensor imaging that can help us look at the connections we saw the decreases in some of the structural Krypton integrity of these white matter connections in adults we also saw decreases in the ability of the functional connections of the certain nodes of the circuit to work well together at adults we're also seeing that in the adolescence and in some of our recent data we're seeing that although some of them some of those differences seem to be present in the adolescents they do seem to be progressing during the adolescent young adult period just a word about suicide I won't be as focused in this talk on it that's a increasingly important part of our program were very dedicated to that work and indeed we're seeing some higher magnitude of some of these changes in the adolescents and young adults who make suicide attempts and in some very early work we're seeing that some of those differences may be predictive we've followed adolescents now for six and seven years the ones who had the highest magnitude of those differences may be the ones who are more likely to go on to make attempts and that would be very important as a clue for prevention okay so in this very last part of the talk I just kind of want to touch on some of the directions we're going so we have some of these places to look in terms of the circuitry and how it might develop and what we now want to do is understand the different mechanisms genetic and environmental that can lead to a cascade of events that ultimately result in these differences in circuitry and the symptoms I think as dr. Kelly talked about in her talk we're all kind of hoping and I think the future is very hopeful that we're moving in a direction towards more personalized treatment approaches so that if you can start to understand how if someone has a certain combination of genes because a different individuals with bipolar disorder there may be different combinations of genes maybe ones that run in families that if you have a particular combination of genes and particular brain changes and symptoms then maybe there are ways to target that individual's biology that individuals makeup to help to best treat them and also towards the question that was asked earlier to also potentially avoid treatments that would not be helpful for them and avoid those side effects so this is just very quickly showing that we've initiated work looking at different genetic variations implicated in bipolar disorder and we are seeing that the risk variations are related to some of the differences in the brain that we're seeing so some clues about genetic effects and then also you'll be hearing much more about this type of work later but we've also looked for example at early child maltreatment abuse or neglect emotional or physical and we also are seeing some overlap in the changes in the brain as we see in the mood disorders and wonder about the potential of those two contributing to some of the brain differences or worsening or differences in the expression of the disorder in terms of treatment as mentioned there's evidence that mood stabilizing treatments can help to grow nerve cells potentially reverse these processes very early work suggests that medication may be able to reverse these processes here's ventral prefrontal gray matter no mood stabilizer higher our mood stabiliser here is ventral prefrontal functioning off medication on on medication here lithium and the hope is that we'll also learn ways to use these treatments to prevent progression and one in particular that we've just started to do and very excited about is trying to use psycho behavioral types of therapies ones where we teach healthy habits regularizing sleep daily activity helping to train adolescents to better regulate their emotions and we hope that that and we have some very preliminary evidence that that can help to strengthen the circuitry and potentially help with some of the symptoms so what I've tried to show you is there's kind of a light on some of the areas that we think are now important in bipolar disorder we have some different developmental processes that we're now think about in terms of targeting treatments medication but also behavioral treatments takes for all of this research as alluded to it takes a village for all of this I'm very grateful to my collaborators as mentioned the central importance of the funding of be PRF in our side as well as under other funding sources thank you great talk yeah we've got a time for maybe one or two a question if we can turn out the lights yes sir Oh I yep yep yep so if I underneath yes if I understand the question the question is recurrent depression major depression just disorder it see if bipolar disorder with recurrent mood episodes you have depression major depression with recurrent mood disorders do we think of those as separate illnesses or similar illnesses or you know or along a spectrum of the same illnesses and that that could potentially have treatment implications whether you pick certain classes of medications that might make things better better or worse and so that's a very interesting and a very you know a topic that it's being vigorously studied and really needs study and it's interesting because there are different thoughts about it internationally so even if you you know in in Europe often there's more thinking that MDD and bipolar disorder or actually you know kind of a long you know more similar and there are medications that can be similarly helpful in both for example lifting can be helpful in both disorders often used a little bit differently but used you know for mood stabilization and bipolar disorder but often to help in major depressive disorder where some of the most you know intractable to treat depressions and we also have we have individuals who have just manic episodes you know that are kind of in the middle of the country of individuals who have one episode many episodes and so I think you know you point well - there's so much heterogeneity in the disorders and we we need so much to get better at understanding that heterogeneity one of the things with some of that genetic work for example that we're trying to do is to try to see if we see that the genes are associated with certain particular changes in the brain that may be and then that's associated with a particular course and I think you bring up an important point not just a cross-sectional view of this order but a course of the disorder that then maybe we can get better at targeting those genes to better help with that particular course that they're related to just one more quick question we we got some great things coming up yes go ahead and give us your question and so you can so the so the question is whether you you know since I mentioned that you can sometimes see just manias you don't necessarily see depressions is that usual so it is the case that depressions are the more frequent episodes overall and bipolar disorder but that said it's very individual and you can see not only can you see you know just meny or just you know depression but also you could see in individuals you know humans love dichotomies but often you see really a mixture of the symptoms and that's a very common presentation so someone has sort of a mixture of maybe they're feeling really just for ik and terrible but they're really energized and so they can have the comment so you kind of see all these combinations one thing that's interesting is there can be some sex differences so women are more likely to have depressive episodes and males manic episodes is there something to that and so you're raising a very important question it seems also to be in a really an important theme of this conference is you know the trying to sort out this heterogeneity where it stems from and that how to target those factors either through prevention or or with better treatments

Channel: Brain & Behavior Research Foundation

Views: 38,887

Keywords: schizophrenia, depression, bipolar disorder, anxiety, autism, post-traumatic stress disorder, ptsd, obsessive-compulsive disorder, ocd, adhd, brain research, narsad grants, symptoms, recovery, behavior research, warning signs, treatments, cure, diagnosis, hope

Id: mUumPkIr17E

Length: 33min 41sec (2021 seconds)

Published: Tue Nov 06 2018